The hepatic metabolism of genetically diabetic mice (C57 BL/Ks-db/db or C 57 BL/Ks-mdb/mdb) will be studied in relation to the development of hyperglycemia, insulin resistance and obesity. Hepatic glycogen synthesis and breakdown and gluconeogenesis will be studied at various ages from 1 week to 3 months using tracer techniques in vivo, liver perfusion or isolated hepatocytes. The responses of these processes and of cyclic AMP levels to glucagon and insulin will also be examined at various ages. These studies will evaluate the role of changes in hepatic carbohydrate metabolism in the development of hyperglycemia and insulin resistance. Hepatic lipogenesis, fatty acid oxidation, ketogenesis and triglyceride synthesis will be studied using analogous techniques to those stated above. These experiments are aimed at determining the role of the liver in the development of obesity. The activities of enzymes involved in these pathways will be assayed in animals showing metabolic alterations. Such changes will be correlated with changes in hormone levels or tissue responses to hormones. BIBLIOGRAPHIC REFERENCES: T.M. Chan and J.H. Exton. Glucose metabolism and insulin sensitivity in livers of genetically diabetic (db/db) mice. Fed. Proc. 34, 334 (1975). T.M. Chan, K.M. Young, N.J. Hutson, F.T. Brumley and J.H. Exton. Hepatic metabolism of genetically diabetic (db/db) mice. I. Carbohydrate metabolism. Amer. J. Physiol. In press.